Helicobacter pylori (H. pylori) is a bacterium that infects the stomachs of around one third of the US population and half of the world population, and is probably the most common human bacterial infection. To accomplish this, H. pylori overcomes the very low pH environment of the stomach via complex mechanisms. Understanding H. pylori adaptation to low pH will have great scientific and medical significance. Towards this end, we will study proteins that regulate pH and gastric cell contact-associated gene expression in H. pylori. We focus on two novel sequence-specific DNA binding proteins. HP0222 and its homolog HP0564, whose functions we established based on our structural and biochemical studies. HP0222 is moderately transcribed under neutral conditions, but becomes up regulated in H. pylori cultured at acidic pH or in contact with gastric cells. We hypothesize that HP0222 and HP0564 are transcriptional regulators that play a role in H. pylori virulence. We propose to find the DNA sequences recognized by these proteins and to determine their effects on the transcription of H. pylori genes. We will pursue three specific aims: 1. consensus DNA sequences recognized by HP0222 and HP0564, 2. structures of HP0222 and HP0564 bound to DNA, 3. HP0222 and HP0564 role in pathogenesis. Completed aims will identify a set of genes and a novel regulatory mechanism important in H. pylori pathogenesis. Genes regulated by HP0222 and HP0564 will be candidates for future gene disruption experiments. [unreadable] [unreadable] Helicobacter pylori is a bacterium that infects the stomachs of around one third of the US population and half of the world population, and is the most common human bacterial infection. It is causatively linked with both common and severe gastrointestinal diseases like duodenal ulcer, gastritis, gastric ulcer, gastric carcinoma and gastric lymphoma. Results of this research will help design novel and specific treatments to eradicate H. pylori without resorting to potent side effect- inducing antibiotics that target universally shared biochemical pathways. [unreadable] [unreadable] [unreadable] [unreadable]